Summary In recent years, opioid use disorder (OUD) and deaths due to opiate overdose (e.g., with heroin, fentanyl, oxycodone) in suburban and rural non-minority groups has created an urgency for approaches to stem this epidemic, but the rise in OUD and opiate overdose deaths has occurred in inner cities at similar rates. Heroin misuse and addiction are persistent problems in African-American communities and in inner cities, and a widely understudied trend is that addiction to opioid medication and heroin has become the major cause of morbidity, crime and infectious disease in a huge segment of the African American population. Despite recent efforts to expand addiction research recruitment to include minorities, significant race disparities persist for African-Americans, and this disparity negatively impacts access to affordable but sophisticated treatment mechanisms available to other groups. OUD disrupts reward processing within the mesocorticolimbic system, a process that is, in part, rooted in genetics. Our preliminary studies suggest that ancestry- specific SNPs may govern addiction behavior in specific groups: African-Americans express the dopamine receptor DRD2A1 allele at double the frequency of European-Americans. Moreover, pharmacogenomics (PGx) testing in a cohort of heroin addicts at our facility reveal a significant 85% frequency of the CYP3A4 *1B allele, the variant which confers rapid metabolism of the treatment drug, buprenorphine, a mu opioid agonist. These ancestry-specific findings are further corroborated by GWAS studies in drug addicted patients, where the intronic SNP in the KAT2B (Lysine acetyl transferase 2B) gene was specifically identified in African-Americans and not in European-American addicts. Based on this scientific premise, we hypothesize that opioid use in African-Americans will be associated with hypodopaminergic alleles that alter the threshold for activating feelings of reward and pleasure within the dopaminergic system, and that these allelic frequencies will differ significantly from European Americans. We propose to develop a targeted system to study genetic risks for reward deficiency using risk gene panel to assign a genetic addiction risk score (GARS), comprehensive surveys to determine quality of life and exposure to stressors and trauma. This system will allow prediction of addiction and relapse potential and delivery of personalized treatment. We further propose to develop a dosing strategy for a Neuroadaptogen- amino-acid therapy (NAAT) that will reduce the incidence of relapse to opioid use. This is a Systematic Medical Approach to Reward Transformation (SMART) for brain health and opioid use disorders in a mostly African-American population in Phase 1 where we will 1) validate the GARS scoring system against PGx data and ethnically and culturally sensitive life situations 2) Assess the effectiveness of the reward system- targeted NAAT as an effective treatment to reduce relapse in genetically identified high and low risk groups and 3) Develop a database: the SMART Clinical Genomic Registry to facilitate management of clinical, social, and genomic data. This approach promotes brain health even in non- opioid users.